SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models
Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan...
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description | Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1's role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs. |
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At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1's role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0230354</identifier><identifier>PMID: 32413029</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anticoagulants ; B cells ; Biology and Life Sciences ; Biomimetics ; Bone cancer ; Bone growth ; Bone marrow ; Bone Neoplasms - metabolism ; Bone Neoplasms - secondary ; Cancer metastasis ; Cancer research ; Cancer-Associated Fibroblasts - metabolism ; Cell Line, Tumor ; Cells, Cultured ; Cellular signal transduction ; Dentistry ; Development and progression ; Enzymes ; Esterases ; Fibroblasts ; Genotype & phenotype ; Growth factors ; Health aspects ; Heparan sulfate ; Heparan Sulfate Proteoglycans - metabolism ; Heparin ; Humans ; Hydrogels ; Hydrogels - chemistry ; Latency ; Macrophages ; Macrophages - metabolism ; Male ; Medicine and Health Sciences ; Metastases ; Metastasis ; Perlecan ; Physical Sciences ; Prostate cancer ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Proteoglycans ; Recurrence (Disease) ; Research and Analysis Methods ; Stromal cells ; Stromal Cells - metabolism ; Sulfates ; Sulfotransferases - metabolism ; Three dimensional models ; Tissue Engineering - methods ; Tissue Scaffolds - chemistry ; Tumors ; Wnt proteins ; Wnt Signaling Pathway ; Xenografts ; Xenotransplantation</subject><ispartof>PloS one, 2020-05, Vol.15 (5), p.e0230354-e0230354</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Brasil da Costa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models</title><author>Brasil da Costa, Fabio Henrique ; Lewis, Michael S ; Truong, Anna ; Carson, Daniel D ; Farach-Carson, Mary C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-44255f6f3bf9e8af7dfa78bb5df5170b7568872f55816a92ad967dcde5f2bde23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Anticoagulants</topic><topic>B cells</topic><topic>Biology and Life Sciences</topic><topic>Biomimetics</topic><topic>Bone cancer</topic><topic>Bone growth</topic><topic>Bone marrow</topic><topic>Bone Neoplasms - metabolism</topic><topic>Bone Neoplasms - secondary</topic><topic>Cancer metastasis</topic><topic>Cancer research</topic><topic>Cancer-Associated Fibroblasts - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cells, 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One</addtitle><date>2020-05-15</date><risdate>2020</risdate><volume>15</volume><issue>5</issue><spage>e0230354</spage><epage>e0230354</epage><pages>e0230354-e0230354</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1's role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32413029</pmid><doi>10.1371/journal.pone.0230354</doi><tpages>e0230354</tpages><orcidid>https://orcid.org/0000-0003-0819-3268</orcidid><orcidid>https://orcid.org/0000-0002-2089-4051</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2020-05, Vol.15 (5), p.e0230354-e0230354 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_2403302536 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Anticoagulants B cells Biology and Life Sciences Biomimetics Bone cancer Bone growth Bone marrow Bone Neoplasms - metabolism Bone Neoplasms - secondary Cancer metastasis Cancer research Cancer-Associated Fibroblasts - metabolism Cell Line, Tumor Cells, Cultured Cellular signal transduction Dentistry Development and progression Enzymes Esterases Fibroblasts Genotype & phenotype Growth factors Health aspects Heparan sulfate Heparan Sulfate Proteoglycans - metabolism Heparin Humans Hydrogels Hydrogels - chemistry Latency Macrophages Macrophages - metabolism Male Medicine and Health Sciences Metastases Metastasis Perlecan Physical Sciences Prostate cancer Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Proteoglycans Recurrence (Disease) Research and Analysis Methods Stromal cells Stromal Cells - metabolism Sulfates Sulfotransferases - metabolism Three dimensional models Tissue Engineering - methods Tissue Scaffolds - chemistry Tumors Wnt proteins Wnt Signaling Pathway Xenografts Xenotransplantation |
title | SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T18%3A59%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=SULF1%20suppresses%20Wnt3A-driven%20growth%20of%20bone%20metastatic%20prostate%20cancer%20in%20perlecan-modified%203D%20cancer-stroma-macrophage%20triculture%20models&rft.jtitle=PloS%20one&rft.au=Brasil%20da%20Costa,%20Fabio%20Henrique&rft.date=2020-05-15&rft.volume=15&rft.issue=5&rft.spage=e0230354&rft.epage=e0230354&rft.pages=e0230354-e0230354&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0230354&rft_dat=%3Cgale_plos_%3EA623985350%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2403302536&rft_id=info:pmid/32413029&rft_galeid=A623985350&rft_doaj_id=oai_doaj_org_article_d3c82d1186f345268ee2261b06ad80e2&rfr_iscdi=true |